Thyroid hormones are critical for normal development and for the maintenance of metabolic homeostasis. As such, thyroid hormones are known to stimulate the metabolism of cholesterol to bile acids and enhance the lipolytic responses of fat cells to other hormones.
Thyroid hormones further affect cardiac function both directly and indirectly, e.g., by increasing the metabolic rate. For example, tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance and increased pulse pressure are all observed in patients with hyperthyroidism.
Disorders of the thyroid gland resulting in decreased levels of thyroid hormones are normally treated by administering either naturally occurring thyroid hormones or analogues thereof that mimic the effects of thyroid hormones. Such analogues are known generically as thyromimetics or thyroid receptor ligands.
Two naturally occurring thyroid hormones, 3,5,3′-triiodo-L-thyronine (also referred to as “T3”), and 3,5,3′,5′-tetraiodo-L-thyronine (also referred to as “T4” or thyroxine), are depicted hereinbelow: 
Generally, T3 is more biologically active than T4, and differs therefrom by the absence of an iodine atom in the 5′ position. T3 may be produced directly, in either the thyroid gland or in peripheral tissues, by removal of the 5′ iodine of T4 by deiodinase enzymes. Synthetic thyroid receptor ligands can be designed to be structurally similar to T3. In addition, naturally occurring metabolites of T3 are known.
As discussed hereinabove, thyroid hormones may affect cardiac functioning, for example, by causing an increase in heart rate and, accordingly, an increase in oxygen consumption. While the increase in oxygen consumption can result in certain desirable metabolic effects, such increase places additional burden on the heart which, in many situations, results in detrimental side effects. Consequently, efforts have been made to synthesize thyroid hormone analogs/mimetics that function to lower lipids and serum cholesterol, but which have reduced adverse cardiac effects.
A variety of thyroid hormone analogs/mimetics are described and referenced hereinbelow, however, additional agents will be known to one of ordinary skill in the art. For example, U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; and 5,061,798 disclose thyroid hormone mimetics, namely, 3,5-dibromo-3′-[6-oxo-3(1H)-pyridazinylmethyl]-thyronines, while U.S. Pat. No. 5,284,971 discloses thyromimetic cholesterol lowering agents, namely, 4-(3-cyclohexyl-4-hydroxy or -methoxy phenylsulfonyl)-3,5 dibromo-phenylacetic compounds. Furthermore, U.S. Pat. Nos. 5,654,468 and 5,569,674 disclose certain lipid lowering agents, namely, heteroacetic acid derivatives, which compete with radiolabeled T3 in binding assays using rat liver nuclei and plasma membrane preparations. Still further, certain oxamic acids and derivatives thereof are known in the art, e.g., U.S. Pat. No. 4,069,343 describes the use of oxamic acids in preventing immediate type hypersensitivity reactions, U.S. Pat. No. 4,554,290 describes the use of oxamic acids to control pests on animals and plants, U.S. Pat. No. 5,232,947 describes the use of oxamic acids to improve damaged cerebral functions of the brain, and European Application Publication No. EP 0 580 550 (also U.S. Pat. No. 5,401,772) discloses oxamic acid derivatives as hypocholesterolemic agents. In addition, certain oxamic acid derivatives of thyroid hormones are known in the art. See, for example, Yokoyama et al., J. Med. Chem., 38 (4), 695-707 (1995), Steele et al., International Congressional Service (Atherosclerosis X) 106, 321-324 (1995), and Stephan et al., Atherosclerosis, 126, 53-63 (1996).
Obesity is a major health risk that leads to increased mortality and incidence of Type 2 diabetes mellitus, hypertension, and dyslipidemia. In the United States, more than 50% of the adult population is overweight, and almost ¼ of the population is considered to be obese. The incidence of obesity is increasing in the United States at a three-percent cumulative annual growth rate. While the vast majority of obesity occurs in the United States and Europe, the prevalence of obesity is also increasing in Japan. The prevalence of obesity in adults is 10-20% in most countries of western Europe. Furthermore, obesity is a devastating disease which can also wreak havoc on an individual's mental health and self-esteem, which can ultimately affect a person's ability to interact socially with others. Unfortunately, the precise etiology of obesity is complex and poorly understood, and societal stereotypes and presumptions regarding obesity only tend to exacerbate the psychological effects of the disease. Because of the impact of obesity on society in general, much effort has been expended in efforts to treat obesity, however, success in the long-term treatment and/or prevention thereof remains elusive.
The thyroid receptor ligands of the present invention can be used to treat obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias (including atrial and ventricular arrhythmias), skin disorders, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, and osteoporosis.
The diabetic disease state is characterized by an impaired glucose metabolism that manifests itself in, inter alia, elevated glucose levels in patients suffering therefrom. Generally, diabetes is classified into two distinct subgroups:                (1) Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), which arises when patients lack α-cells producing insulin in their pancreatic glands, and        (2) Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with, inter alia, impaired β-cell function.        
At present, Type 1 diabetic patients are treated with insulin, while the majority of Type 2 diabetic patients are treated with hypoglycemic agents, such as sulfonylureas that stimulate β-cell function, with other agents that enhance the tissue selectivity of the patients towards insulin, or with insulin itself. Unfortunately, the use of insulin currently requires multiple daily doses, normally administered by self-injection, with determination of the proper dosage of insulin requiring frequent estimations of the sugar in urine or blood, performed either by the patient or the administering physician. The unintended administration of an excess dose of insulin can result in hypoglycemia, with adverse effects ranging from mild abnormalities in blood glucose to coma, or even death. Although hypoglycemic agents agents such as sulfonylureas have been employed widely in the treatment of NIDDM, this treatment is, in many instances, not completely satisfactory. In a large number of NIDDM patients, sulfonylureas have proven ineffective in normalizing blood sugar levels of patients, thereby leading to an increased risk of acquiring diabetic complications. Also, many patients gradually lose the ability to respond to treatment with sulfonylureas and are thus gradually forced into insulin treatment. Since many extant forms of diabetic therapy have proven ineffective achieving satisfactory glycemic control, there continues to be a great demand for novel therapeutic approaches.
Atherosclerosis, a disease of the arteries, is recognized to be a significant risk factor in the cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well established. The earliest stage in this sequence is the formation of so-called “fatty streaks” in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. It is further postulated that most of the cholesterol found within the fatty streaks, in turn, give rise to development of so-called “fibrous plaques,” which consist of accumulated intimal smooth muscle cells laden with lipid which are surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. The cells plus their matrix form a fibrous cap covering a deeper deposit of cell debris and additional extra-cellular lipid, comprising primarily free and esterified cholesterol. The fibrous plaque accumulates gradually, and is likely in time to become calcified and necrotic, advancing to a so-called “complicated lesion,” which accounts for arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm characterizing the condition of advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, medical professionals have placed a renewed emphasis on lowering plasma cholesterol levels, particularly low-density lipoprotein cholesterol, as an essential step in prevention of CVD. The upper limits of normal plasma cholesterol levels are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, particularly affecting members of the male population. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population and, in particular, diabetic individuals, is therefore of exceptional medical importance.
Hypertension, or high blood pressure, is a condition that occurs in the human population as a condition ancillary to various other disorders such as renal artery stenosis, pheochromocytoma or endocrine disorders. However, hypertension is also evidenced in many patients in whom the causative agent or disorder is unknown. While such so-called “essential” hypertension is often associated with disorders such as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders has not yet been elucidated. Additionally, many patients display the symptoms of high blood pressure in the complete absence of any other signs of disease or disorder.
It is known that hypertension can directly lead to heart failure, renal failure and stroke, i.e. brain hemorrhaging, which conditions are capable of causing immediate death in a patient. Hypertension can also contribute to the development of atherosclerosis and coronary disease which conditions gradually weaken a patient and can also lead to death.
The exact cause of essential hypertension is unknown, though a number of factors are believed to contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, unregulated hormone release, especially those affecting the renin, angiotensin, and aldosterone systems, excessive salt and water due to kidney malfunction, wall thickening and hypertrophy of the vasculature resulting in constricted blood vessels, and certain genetic factors.
The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus, a broad range of beta-blockers, vasoconstrictors, angiotensin converting enzyme (ACE) inhibitors and the like have been developed and marketed as antihypertensives. The treatment of hypertension utilizing these compounds has proven beneficial in the prevention of short-interval deaths such as heart failure, renal failure and brain hemorrhaging.
Hypertension has been associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary actions are to promote glucose utilization, protein synthesis and the formation and storage of neutral lipids, also acts, inter alia, to promote vascular cell growth and increase renal sodium retention. These latter functions, which are known causes of hypertension, can be accomplished without affecting glucose levels. Peripheral vasculature growth, for example, can cause constriction of peripheral capillaries while sodium retention increases blood volume. Thus, the lowering of insulin levels in hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels, thereby alleviating hypertension.